The immune system plays an important role in host defense. In the treatment of leukocyte activation-associated disorders is often desirable to attenuate the immune response. Such disorders include the immune response incurred by transplantation or diseases improved by decreased T-cell activation and proliferation. It is accepted that agents that inhibit T-cell proliferation may be useful in the treatment of the aforementioned disorders.
A number of agents demonstrate clinical or therapeutic utility by attenuating or modulating the immune system. Such agents include Cyclosporin A (“CsA”), azathioprine, tacrolimus, sirolimus and mycophenolate mofetil. However, these agents often demonstrate a relatively high incidence (25 to >50%) of multiple unique liabilities during clinical or therapeutic use. For example, CsA therapy is associated with nephrotoxicity, azathioprine therapy is associated with leukopenia, and tacrolimus therapy is associated with undesirable effects on the central nervous system. Also, sirolimus therapy is associated with hypertension, hyperlipidemia and hypercholesterolemia, and mycophenolate mofetil therapy is associated with diarrhea.
The overproduction of cytokines, such as TNF-α, is also implicated in a wide variety of leukocyte activation-associated disorders, including rheumatoid arthritis (RA), psoriasis, multiple sclerosis, inflammatory bowel disease, endotoxin shock, osteoporosis, Alzheimer's disease and congestive heart failure, among others. See e.g., Henry et al., Drugs Fut., 24:1345–1354 (1999); Salituro et al., Curr. Med. Chem., 6:807–823 (1999). There is convincing evidence in human patients that cytokine protein antagonists can provide treatment for these disorders. See e.g., Rankin et al., Br. J. Rheumatol., 34:334–342 (1995) (monoclonal antibody to TNF-α—Enbrel®); and Moreland et al., Ann. Intern. Med., 130:478–486 (1999) (soluble TNF-α receptor-Fc fusion protein—etanercept). Accordingly, it is accepted that agents demonstrating TNF-α inhibitory activity are useful for the treatment of leukocyte activation-associated disorders.
As none of the current treatments provide complete relief of symptoms and are often associated with various liabilities, new agents and improved methods for treating leukocyte activation-associated disorders are needed.